Deuterium-enriched pyridinonecarboxamides and derivatives

ABSTRACT

The present invention relates to deuterium-enriched pyridinone carboxamides and their derivatives of the formula I, and pharmaceutically acceptable salts thereof, 
     
       
         
         
             
             
         
       
     
     are partial or full agonists of serotonin (5-Hydroxytryptamine or 5-HT 4 ) receptor subtype 4, and are useful compounds for the prevention and treatment of Alzheimer&#39;s disease, cognitive and memory dysfunction, mild cognition impairment, memory decline, cognitive impairment associated with schizophrenia, cognitive impairment associated with age-related dementia or Alzheimer&#39;s disease, cognitive impairment associated with post-coronary bypass surgery, attention deficit hyperactivity disorder, speech improvement in autistic children, sleep apnea in Alzheimer&#39;s patients, irritable bowel syndrome, gastroesophageal reflux disease, Crobn&#39;s disease, emesis, nausea, vomiting, prokinesia, non-ulcer dyspepcia, anxiety, depression, pain, migraine, urinary incontinence, arterial fibrillation, arrhythmia, ischemic stroke, gastric emptying disorders, gastritis, gastrointestinal disorders, feeding disorders, obesity, anorexia, constipation, respiratory depression, and erectile dysfunction.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority benefit under 35 U.S.C. articlesection 119(e) of U.S. Provisional Patent Application Ser. No. U.S.61/271,720 filed 27 Jul. 2009. The disclosure of this application isincorporated herein by reference.

SUMMARY OF THE INVENTION

The present invention is concerned with deuterium-enriched pyridinonecarboxamides and derivatives thereof of formula I,

Wherein,

-   -   R₁ and R₂ are independently, H, D (deuterium with enrichment of        1%-100%), F, Cl, CD₃ (methyl-d₃), CH₂CD₃, CD₂CD₃, CH₂CH₂CD₃, OD,        OCD₃;    -   R₃, R₄ and R₅ are independently H, D (Deuterium with 1%-100%),        CD₃, cyclopropyl-d (c-Pr-d₁-d₅), R₃ joined with R₄ or R₅ to form        cyclopropane ring;    -   R₆, R₇, R₃, R₉, R₁₀ and R₁₁ are independently, H, D (Deuterium        with 1%-100% enrichment);    -   R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, and R₂₁ are        independently H, D (Deuterium with 1%-100% enrichment        incorporated), F, Cl, CH₃, CD₃, CF₃, CH₂CH₃, CD₂CD₃, CH₂CF₃,        CF₂CF₃, CH₂CH₂CH₃, CD₂CD₂CD₃, OH, OCH₃, OCD₃, OCF₃, CN; CO₂CH₃,        CO₂CD₃, OH, OD, OCF₃, OCD₃, NO₂, SO₂R(R is C1-C3 alkyl, C1-C6        cycloalkyl);    -   R₂₂ is H, D (deuterium), CD₃;    -   R₂₃ is H, D, CD₃;    -   X, Y and Z are independently, S, N, C, O, and C═C.

The compounds of formula I and acceptable pharmaceutical salts thereofare 5-HT₄ receptor agonists (partial or full agonists) and are usefulfor the prevention and treatment of Alzheimer's disease, cognitive andmemory dysfunction, mild cognition impairment, memory decline, cognitiveimpairment associated with schizophrenia, cognitive impairmentassociated with age-related dementia or Alzheimer's disease, cognitiveimpairment associated with post-coronary bypass surgery, attentiondeficit hyperactivity disorder, speech improvement in autistic children,sleep apnea in Alzheimer's patients, irritable bowel syndrome,gastroesophageal reflux disease, Crohn's disease, emesis, nausea,vomiting, prokinesia, non-ulcer dyspepcia, anxiety, depression, pain,migraine, urinary incontinence, arterial fibrillation, arrhythmia,ischemic stroke, gastric emptying disorders, gastritis, gastrointestinaldisorders, feeding disorders, obesity, anorexia, constipation,respiratory depression, and erectile dysfunction.

One of the objectives of the present invention is to provide deuteriumenriched compounds of formula I or a pharmaceutically acceptable saltthereof.

It is another objective of the present invention to providepharmaceutical compositions comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of at least one of thedeuterium enriched compounds of the present invention or apharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a fully (all Hatoms replaced with deuterium) or partially (one or more H atoms of acompound replaced with deuterium) deuterated compound of formula I or apharmaceutically acceptable salt thereof.

It is another object of the present invention to provide achlorine-substituted (R₁=Cl) deuterium-enriched compound derivative offormula I or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide aflorine-substituted (R_(I)=F) deuterium-enriched compound derivative offormula I or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a method fortreating Alzheimer's disease comprising administering to a host in needof such treatment a therapeutically effective amount of at least one ofthe compounds of the present invention or a pharmaceutically acceptablesalt thereof.

It is another object of the present invention to provide a method fortreating cognitive impairment and/or cognitive dysfunction comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a method fortreating memory impairment, or memory decline or memory dysfunctioncomprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a method fortreating memory impairment, or memory decline or memory dysfunctionassociated with schizophrenia comprising administering to a host in needof such treatment a therapeutically effective amount of at least one ofthe compounds of the present invention or a pharmaceutically acceptablesalt thereof.

It is another objective of the present invention to provide the use of anovel compound of formula I or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for the treatment ofAlzheimer's disease and related cognitive and memory dysfunctions,cognitive and memory impairment associated with schizophrenia, andfrontotemporal dementias.

It is another object of the present invention to provide a method fortreating various disease by compounds of formula I, as a monotherapy orin combination with other cognition and memory enhancing medicamentssuch as acetylcholine esterase inhibitor, donepezil or a NMDA glutamatereceptor blocker, memantine, comprising administering to a host in needof such treatment a therapeutically effective amount of at least one ofthe compounds of the present invention or a pharmaceutically acceptablesalt thereof.

BACKGROUND OF THE INVENTION

Neurotransmitter serotonin or 5-Hydroxytryptamine (5-HT) is abundantlydistributed in the central nervous system, including hippocampus andfrontal cortex. 5-HT receptors are a family of G-protein coupledreceptors, characterized with 7-transmembrane helices and presently havefourteen known receptor subtypes, some of which exist as multiple splicevariants [D. L. Murphy, A. M. Andrews, C. H. Wichems, Q. Li, M. Tohdaand B. Greenberg, J. Clin. Psychiatry, 1998, 59 (suppl. 15), 4]. 5-HTinfluences a number of physiological functions and is implicated in alarge number of central nervous system disorders and neurodegenerativediseases [W. E. Childers, Jr. and A. J. Robichaud, Ann. Rep. Med. Chem.2005, 40, 17].

The 5-HT₄ receptors are a member of the superfamily of G-protein coupledreceptors with seven transmembrane (7™) domains coupled to a G-proteinwhich is positively coupled to adenylate cyclase. The 5-HT₄ receptorsare expressed in a wide variety of tissues, including the human brainand the rodent brain, and human, dog, pig and rodent gastro-intestinaltract, and the pig and human heart. In the human brain, the presence of5-HT₄ receptors has been shown in basal ganglia and in the caudateputamen nuclei, where the density is the highest [Bonacenture, Hall,Gommersen, Cras, langlois, Jurzak, Leysen, Synapse, 2000, 36, 35]. Inthe mammalian brain, the 5-HT₄ receptors contribute to dopaminesecretion and regulate learning and long-term memory via themodification of acetylcholine release. In the central nervous system ofguinea-pigs and rats, 5-HT₄ receptors are expressed in two anatomicaland functional structures: the extrapyramidal motor system and themesolimbic system [Patel, Roberts, Moorman, Reavill, Neuroscience, 1995,69, 1159; Grossman, Kilpatrik, Bunce, Br. J. Pharmacol. 1993, 109, 618].

In the peripheral tissues, the 5-HT₄ receptors have proven to regulategastro-intestinal tract motility, intestinal electrolyte secretion,adrenal secretion of corticosteroids, bladder contraction and atriumcontractility. Significant advances have been made in the 5-HT₄ receptorstudies during the past decade that culminated in the development of5-HT₄ agonists and partial agonists, e.g. Tegaserod, for the treatmentof irritable bowel syndrome [Giger, Mattes, Pfannkuche, Ann. Rep Med.Chem. 2007, 42, 195].

The 5-HT₄ receptors are involved in a wide variety of central andperipheral disorders, including neurodegenerative disorders such asAlzheimer's disease, cognition disorders, irritable bowel syndrome,nausea, emesis, vomiting, prokinesia, gastroesophageal reflux disease,nonulcer dyspepsia, depression, anxiety, urinary incontinence, migraine,arrhthymia, atrial fibrillation, ischemic stroke, gastritis, gastricemptying disorders, feeding disorders, gastrointestinal disorders,constipation, erectile dysfunction, and respiratory depression.

The role of the 5-HT₄ receptor has been implicated in the pathology ofAlzheimer's disease and related cognitive function [J. Bockaert, S.Claeyseen, V. Compan and A. Dumuis. Curr. Drug. Targets: CNS & Neurolog.Disorders, 2004, 3, 39; P. C. Moser, O. E. Bergis, S. Jegham, A.Lochead, E. Duconseille, T. Elee, J.-P. Terranova, D.Caille, I.Berque-Bestel, F. Lezoualch, R. Fischmeister, A. Dumuis, J. Bockaert, G.Pascal, P. Soubrie and B. Scatton, J. Pharmacol. Exp. Ther. 2002, 302,731]. A recent report provides evidence from transgenic animal studiesthat supports the finding that the 5-HT₄ receptor is a novel target forcognitive enhancement and that only a partial agonist is needed forproducing the beneficial effect in increasing cognition function.Moreover, the 5-HT₄ receptor remains functional even in the presence ofexcess of A□ □ for Alzheimer's drug discovery [J. P. Spencer, J. T.Brown, J. C. Richardson, A. D. Medhurst, S. S. Sehmi, A. R. Calver, A.D. Randall, Neuroscience, 2004, 129, 49]. Stimulation of the 5-HT₄receptor promotes an increase in the production and release ofacetylcholine (ACh) in the brain unlike the cholinesterase inhibitorsthat prevent degradation of ACh for symptomatic improvement inAlzheimer's disease patients. The activation of 5-HT4 receptor alsoleads to secretion of the soluble form of amyloid precursor protein(sAPPα), and decrease in Aβ levels via promoting the a-secretase pathway[M. Cachard,-Chastel, F. Lezoualc'h, I. Dewachter, C. Delomenie, S.Croes, H. Devijver, M. Langlois, F. V. Leuven, S. Sicsic, and A. M.Gardier. Brit. J. Pharmacol. 2007, 150, 883]. Evidence in in vivo ratstudies of the role of activation of 5-HT4 receptor in the production ofsAPPαhas recently been reported [S. Cho and Y. Hu, Exper. Neurology,2007, 203, 274]. The protein, sAPPα is neuroprotective, enhances memory,increases NGF and competes with amyloidogenic (insoluble) APP peptides.Considering the significant evidence reported, it is evident that 5-HT₄receptor agonists may have potential not only in the treatment ofAlzheimer's disease but also modification of the disease by slowing andinhibiting its progression [F. Lezoualc'h, Exper. Neurology, 2007, 205,325].

The novel compounds of formula I have 5-HT₄ partial agonist activityand/or full agonist activity, inverse agonist activity and antagonistactivity and have applications as safer and effective therapeutic drugsfor the treatment of Alzheimer's disease and age-related cognitive andmemory dysfunction and cognitive and memory impairment associated withschizophrenia. These compounds may also have applications in thetreatment of gastrointestinal disorders including irritable bowelsyndrome, Crohn's disease, gastroesophageal reflux disease, emesis,nausea, vomiting, prokinesia, non-ulcer dyspepcia, anxiety, depression,pain, migraine, urinary incontinence, arterial fibrillation, arrhythmia,ischemic stroke, gastric emptying disorders, gastritis, gastrointestinaldisorders, feeding disorders, obesity, anorexia, constipation,constipation, respiratory depression, and erectile dysfunction.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of formula 1, theirpharmaceutically acceptable salts, compositions and uses thereof as5-HT₄ partial agonists, or 5-HT₄ full agonists, 5-HT₄ inverse agonists,5-HT₄ antagonists, as mono therapy for treating, preventing or curingAlzheimer's disease, memory conditions, cognition disorders, anddepression, or in combination with existing therapies.

Deuterium (D or ²H) is a stable isotope non-radioactive isotope ofhydrogen (H) and has an atomic weight of 2.0144. Hydrogen occursnaturally as a mixture of the isotopes ¹H, D (²H), and T (³H or tritium)and the natural abundance of deuterium is 0-015%. One of ordinary skillin the art recognizes that in all compounds containing H atom, Hactually represents a mixture of H and D, with about 0-015% of D. So,compounds with a level of D that has been enriched to be greater thanits natural abundance of 0.015%, should be considered unnatural and as aresult novel as compared to their corresponding non-enrichedcounterparts.

The carbon-hydrogen bonds contain a naturally occurring distribution ofhydrogen isotopes, namely ¹H or protium (about 99.9844%), ²H ordeuterium (D) (about 0.0156%), and ³H or tritium (in the range betweenabout 0.5 and 67 tritium atoms per 10¹⁸ protium atoms). Higher levels ofdeuterium incorporation produce a detectable Kinetic Isotope Effect(Werstiuk, N. H.; Dhanoa, D. S.; Timmins, G. Can J. Chem. 1979, 57,2885; Werstiuk, N. H.; Dhanoa, D. S.; Timmins, G. Can J. Chem. 1983, 61,2403), that could improve the pharmacokinetic, pharmacologic and/ortoxicologic parameters of compounds of formula I in comparison tocompounds having naturally occurring levels of deuterium and theircorresponding hydrogen (protium) analogs. The present inventiondisclosed herein describes novel compounds of formula I containinghigher content of deuterium (>1%), synthesis and uses thereof as 5-HT₄partial agonists and/or full agonists and inverse agonist andantagonists for the treatment of central nervous system diseasesincluding Alzheimer's disease, Parkinson's disease, anxiety, depression,schizophrenia, insomnia, nausea, emesis, epilepsy, pain and others.Suitable modifications of certain carbon-hydrogen bonds intocarbon-deuterium bonds may generate novel substituted pyridinonecarboxamides with unexpected and non-obvious improvements ofpharmacological, pharmacokinetic and toxicological properties incomparison to the non-isotopically enriched 5-HT₄ agonist, fullagonists, inverse agonists or antagonists. This invention relies on thejudicious and successful application of chemical kinetics to drugdesign. Deuterium incorporation levels in the compounds of the inventionare significantly higher than the naturally-occurring levels and aresufficient to induce at least one substantial improvement as describedherein. All percentages given for the amount of deuterium (D or d)present are mole percentages.

Deuterium enrichment” refers to the percentage of incorporation ofdeuterium at a given site on the molecule instead of a hydrogen atom.For example, deuterium enrichment of 1% means that in 1% of molecules ina given sample a particular site is occupied by deuterium. Because thenaturally occurring distribution of deuterium is about 0.0156%,deuterium enrichment in compounds synthesized using non-enrichedstarting materials is about 0.0156%.

It can be a significant synthetic challenge to produce 100% deuterium ata specific site of a compound. When 100% deuteration is recited or adeuterium atom is specifically shown in a chemical structure of acompound, a small amount of deuterium may still be present. Higherlevels of deuterium content in a compound can be produced either byHydrogen-Deuterium (H-D) exchange or by synthesizing the compound forspecific deuteration. The H-D exchange is readily achieved in case of Hatoms attached to heteroatoms for example in cases of carboxylic acids(COOH), sulfonamides (SO₂NH₂), alcohols (OH), basic amines (NH₂), etc.However, these incorporated D attached to hetero atoms (O, N, S) etc,readily revert back to H upon exposure to water or any acidic compoundscontaining H atoms. The preferred deuterium containing compounds are theones which contain D directly attached to carbon atoms of the structureof the compounds of this invention.

In some embodiments, the deuterium enrichment in the compounds of thepresent invention is greater than 4%, 5%, 6%, 7%, 8%, 9% or 10%. Inother embodiments, the deuterium enrichment in the compounds of thepresent invention is greater than 20%. In further embodiments, thedeuterium enrichment in the compounds of the present invention isgreater than 50%. In some embodiments, the deuterium enrichment in thecompounds of the present invention is greater than 70%. In someembodiments, the deuterium enrichment in the compounds of the presentinvention is greater than 90%.

This invention is concerned with deuterium-enriched compounds ofstructural formula I,

or a pharmaceutically acceptable salt thereof, wherein,

-   -   R₁ and R₂ are independently, H, D (deuterium with enrichment of        1%-100%), F, Cl, CD₃ (methyl-d₃), CH₂CD₃, CD₂CD₃, CH₂CH₂CD3, OD,        OCD₃;    -   R₃, R₄ and R₅ are independently H, D (Deuterium with 1%-100%),        CD₃, cyclopropyl-d (c-Pr-d₁-d₅), R₃ joined with R₄ or R₅ to form        cyclopropane ring;    -   R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are independently, H, D (Deuterium        with 1%-100% enrichment);    -   R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, ^(R17), R₁₈, R₁₉, R₂₀, and R₂₁ are        independently H, D (Deuterium with 1%-100% enrichment        incorporated), F, Cl, CH₃, CD₃, CF₃, CH₂CH₃, CD₂CD₃, CH₂CF₃,        CF₂CF₃, CH₂CH₂CH₃, CD₂CD₂CD₃, OH, OCH₃, OCD₃, OCF₃, CN; CO₂CH₃,        CO₂CD₃, OH, OD, OCF₃, OCD₃, NO₂, SO₂R (R is C1-C3 alkyl, C1-C6        cycloalkyl);    -   R₂₂ is H, D (deuterium), CD₃;    -   R₂₃ is H, D, CD₃;    -   X, Y and Z are independently, S, N, C, O, and C═C.    -   Pharmaceutically acceptable salts selected from the group        consisting of potassium, sodium, calcium, magnesium, lithium,        hydrochloride, acetate, acetate, trifluoroacetate, mesylate,        maleate, brosylate, fumarate, citrate, tartarate, salts;    -   A pharmaceutical composition comprising the compound of formula        I and a pharmaceutically acceptable carrier.

DEFINITIONS

-   -   The examples provided in the definitions present in this        application are non-inclusive unless otherwise stated. They        include but are not limited to recited examples. The compounds        of the present may have various isomers including all        streoisomers of asymmetric atoms and geometric, tautomeric or        rotamers, and all isomers are considered to be part of the        present invention. All processes used to prepare compounds of        the present invention and intermediates made therein are        considered to be part of the present invention.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of the pharmaceutically acceptablesalts include, but not limited to, mineral or organic acid salts of thebasic residues. The pharmaceutically acceptable salts include but notlimited to potassium, sodium, calcium, magnesium, lithium, HCl, HBr, HI,acetic, trifluoroacetic, citric, ascorbic, benzoin, methanesulfonic,benzenesulfonic, bicarbonic, carbonic, ethane disulfonic, edetic,fumaric, maleic, lactic, malic, mandelic, gluconic, glutamic, glycolic,glycollyarsanilic, lauryl, hexylresorcinic, hyrdabamic, hydroxymaleic,hydroxynaphthoic, isethionic, lactobionic, napsylic, nitric, oxalic,pamoic, pantothenic, phenyllacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, tolouenesulfonic, andp-bromobenzenesulfonic.

General Methods for Preparation of Deuterium-Enriched Compounds ofFormula I

The deuterium-enriched compounds of formula I are prepared as describedin Scheme 1 and 2. The compounds containing deuterium at theheteroatoms, oxygen and nitrogen are prepared by treating precursor(e.g. OH, or CONH, SO₂NH) with deuterium oxide or deuterated aceticacid-d₁ or d₄ (CH₃OD or CD₃OD). The incorporation of deuterium (directlyattached to carbon atom of the compound) into the chemical structure ofthe compound is achieved by using various synthetic chemical methods asdescribed below or extension of the methods available.

-   -   (1) Reductive amination between a carbonyl group and an        appropriate amine using a deuterated reducing agent e.g.        triacetoxy sodium borohydride (NaBH(OAc)₃ or sodium        tetradeuteride, lithium aluminum deuteride or sodium        cyanodeuteride and other nucleophilic deuteride (hydride) agents        available commercially or in the literature.    -   (ii) Electrophilic addition or aromatic substitution of        unsaturated C═C double bonds or aromatic or heteroaromatic ring        system    -   (iii) Deuterium atom exchange for H atom of an aromatic ring        system under high reaction temperature conditions.    -   (v) Hydrogen-Deuterium (H-D) exchange of H atoms bonded to        heteroatoms, O, N, COOH, SO₂NH etc.

The general synthetic methods used for the preparation of compounds ofthis invention are described in Scheme 1 and Scheme 2.

The key intermediates, are 4, 5, prepared from the appropriatelydesigned deuterated aldehyde 1, using steps A and B.

Step A:

To a solution of acetaldehyde-d₄ ₁ in toluene is added 1.2 equivalent ofethyl cyanoacetate 2 (2.2 g) and ammonium acetate followed by aceticacid. The mixture is refluxed for 12 h under nitrogen using Dean-Starkapparatus. After cooling to room temperature by allowing it to stand,the reaction mixture is concentrated using rotary evaporator undervacuum to remove solvent. To the concentrated residue, was added waterand the adduct product 3 is extracted with ethyl acetate. The combinedorganic layer is dried over anhydrous sodium sulfate or anhydrousmagnesium sulfate and concentrated under vacuum. The resulting product 3obtained as such is used for the next step.

Step B.

Morpholine is added to 3 (12.4 g) in ethanol (15 mL) followed byaddition of sulfur in slight excess under nitrogen atmosphere and thesuspension is reflux with stirring for 12 h. After cooling to roomtemperature, the reaction mixture is concentrated in vacuum and theproduct 4 is extracted with ethyl acetate from acqueous phase. Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand the filtrate is concentrated in vacuum. Ethyl2-Aminothiophene-3-carboxylate 4 was purified by column chromatographyusing mixture of ethyl acetate and hexane.

Step C:

The Ethyl 2-amino thiocarboxylate 4 is converted to the N-alkylatedanalog by reductive amination of 4 with hexadeutero acetone in thepresence of acetic acid in dichloromethane using sodium triacetoxyborodeuteride as illustrated in Scheme 1 above. The compound 4 is mixedwith acetone-d₆ in methylene chloride and the mixture is stirred withacetic acid. The reducing agent sodium triacetoxy borohydride-d₁ isadded to the mixture and the resulting mixture stirred until thereaction is completed as monitored by thin layer chromatography. TheN-isopropyl-d₁ alkylated product 5 is purified by flash columnchromatography using ethyl acetate hexane as the eluting solventmixture.

Step D:

The intermediate 7, another penultimate fragment of the active compoundsof this invention is produced by reductive amination of the appropriatepiperidine 6 (fully deuterated or partially deuterated piperidine orsubstituted 4-methyl-piperidine, etc.) with either sodiumtriacetoxyborohydride or sodium triacetoxyborodeuteride-d₁ (or sodiumtriacetoxyborohydride) with the appropriately selected N-protectedpropanal (N-protected propanaldehyde).

The alkylated piperidne intermediate 7 is also produced by alkylatingpiperidine with N-phthalidomido-propyl bromide or N-Boc-propyl bromideor N-CBz propylbromide by refluxing the reaction mixture in toluene.

Step E:

The alkylated piperidine 8 is obtained by deprotection of theintermediate 7. The N-protecting group of 7 is removed by treating itwith a suitable reagent e.g. hydrazine in ethanol for removal ofphthalidomido group, trifluoroacetic acid for removal of Boc andcatalytic hydrogenation for the removal of CBz group.

Step F:

The ethyl aminoester intermediate 5 is converted to the cyclic anhydrideintermediate 9 via saponification to the corresponding acid followed byits treatment with triphiosgene.

Step G:

The interemediate 9 produces the pivotal intermediate ethylβ-hydroxypiperidone carboxylate 10 upon treatment with ethyl malonate inthe presence of NaH (sodium hydride) in N,N-Dimethylformamide.

Steps A through G are utilized to produce the various compounds offormula I in which the thiophene unit of 10 is varied to thecorresponding deuteated or undeuterated region-isomeric thiophenes,thiazoles, oxazoles, pyrazoles, triazoles and benzene derivatives.

Step H:

The ethyl pyridinone carboxylate 10 is refluxed with3-aminopropyl-1-piperidine 8 in toluene to produce the correspondingdesired coupled product, pyridinonecarboxamide 11.

Step I:

The pyridinonecarboxamide 11 is then converted to the correspondingN-deuterated carboxamide by treating with deuterated methanol(CD₃OD-d₄), which then is converted into the desired salt form upon itstreatment with an appropriate base or acid. The pyridinonecarboxamide 11is transformed into the salt form 12, a compound of formula I, bytreating with potassium t-butoxide to yield its potassium salt, orsodium methoxide to give its sodium salt. 11 is treated withhydrochloric acid in ether to produce its HCl salt.

Step J:

The regioisomeric aminothiophene carboxylate 15 of the correspondingcompound 4 is produced from the treatment of carbonyl compound 13 withphosphien oxychloride (POCl₃) in DMF and hydroxylamine to give2-chloroacrylonitrile 14 as shown below in Scheme 2.

Step K:

Treatment of 14 with thioglycolic acid in methanol with sodium methoxideproduces the target ethyl aminothiophene carboxylate 15 as shown belowin Scheme 2.

Various compounds of formula I containing 15 as one of the key fragmentsare produced by utilizing the step C through step I as given above forScheme 1.

Similarly, using Steps A through Step I are utilized to produce variousother compounds of formula I containing 2-halothiophenes, thizole,oxazole, triazole or pyrazole, starting from the corresponding2-amino-3-carboxylates or 3-amino-2-carboxylate as readily availablestarting materials.

EXAMPLES

Given below in Table 1 are compounds that are representative examples ofthe present invention.

TABLE 1 Examples of novel compounds of this invention.

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation, numerous equivalents to the specificreagents can be utilized to produce compounds of the invention. Numerousmodifications and variations of the present invention are possible andtherefore it is understood that within the scope of the appended claims,the invention may be practiced otherwise that as specifically describedherein. Other aspects, advantages and modifications are within the scopeof the invention.

What is claimed is:
 1. A deuterium-enriched compound of formula I, or apharmaceutically acceptable salt thereof,

wherein: R₁ and R₂ are independently, H, D (deuterium with enrichment of1%-100%), F, Cl, CD₃ (methyl-d₃), CH₂CD₃, CD₂CD₃, CH₂CH₂CD3, OD, OCD₃;R₃, R₄ and R₅ are independently H, D (Deuterium with 1%-100%), CD₃,cyclopropyl-d (c-Pr-d₁-d₅), R₃ joined with R₄ or R₅ to form cyclopropanering; R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are independently, H, D (Deuteriumwith 1%-100% enrichment); R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀,and R₂₁ are independently H, D (Deuterium with 1%-100% enrichmentincorporated), F, Cl, CH₃, CD₃, CF₃, CH₂CH₃, CD₂CD₃, CH₂CF₃, CF₂CF₃,CH₂CH₂CH₃, CD₂CD₂CD₃, OH, OCH₃, OCD₃, OCF₃, CN; CO₂CH₃, CO₂CD₃, OH, OD,OCF₃, OCD₃, NO₂, SO₂R(R is C1-C3 alkyl, C1-C6 cycloalkyl); R₂₂ is H, D(deuterium), CD₃; R₂₃ is H, D, CD₃; X, Y and Z are independently, S, N,C, O, and C═C.
 2. A deuterium enriched compound of claim 1 or apharmaceutically acceptable salt thereof, wherein: R₁-R₂₃ are selectedfrom H and D; and the abundance of deuterium is at least 1%, 2%, 3%, 4%,5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%,20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%,34%, 35%, 36%, 37%, 38% , 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%,48%, 49%, 50%, 51%, 52%, 53%, 545, 55%, 56%, 57%, 58%, 59%, 60%, 61%,62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 755,76%, 77%, 78%, 79%, 80%, 81%, 81%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100%; X, Y, and Zare independently selected from S, C, N, O, C═C.
 3. A deuterium enrichedcompound of claim 1 or a pharmaceutically acceptable salt thereof,wherein: R₁-R₂₃ are selected from H and D; and the abundance ofdeuterium is at least 1% , 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%,12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%,26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 365, 37%, 38%, 39%,40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%,545, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 755, 76%, 77%, 78%, 79%, 80%, 81%,81%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99% and 100%.
 4. A deuterium-enriched compound of claim 1or a pharmaceutically acceptable salt thereof, wherein the deuteriumcontent of the compound is greater than the natural abundance ofdeuterium of the corresponding hydrogen atoms containing analog.
 5. Adeuterium enriched compound of claim 1, or pharmaceutical acceptablesalts thereof wherein a compound is selected from examples 1 through 80of compounds shown in Table 1 given in the present invention.
 6. Adeuterium enriched compound of claim 1,6,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propryl)thieno{2,3-b]pyridine-5-carboxamidepotassium salt.


7. A deuterium enriched compound of claim 1,6,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propryl)thieno{2,3-b]pyridine-5-carboxamidepotassium salt.


8. A deuterium enriched compound of claim 1, specifically,6,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propryl)thieno{2,3-b]pyridine-5-carboxamidepotassium salt.


9. A deuterium enriched compound of claim 1,6,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propryl)thieno{2,3-b]pyridine-5-carboxamidepotassium salt.


10. A deuterium enriched compound of claim 1,4,5-Dihydroxy-7-hydroxy-4-isopropyl(d-7)-5-oxo-N-(3-(piperidin-1-yl)propryl)thieno[3,2-b]pyridine-6-carboxamidepotassium salt.


11. A deuterium enriched compound of claim 1,1,2-Dihydroxy-4-hydroxy-1-isopropyl(d-7)-2-oxo-N-(3-(piperidin-1-yl)propryl)thieno[3,4-b]pyridine-3-carboxamidepotassium salt.


12. A deuterium enriched compound of claim 1,4,5-Dihydro-7-hydroxy-4-isopropyl-5-oxo-N-(3-(piperidin-1-yl)propyl)thiozolo[5,4-b]pyridine-6-carboxamidepotassium salt.


13. A deuterium enriched compound of claim 1,4,5-Dihydro-7-hydroxy-4-isopropyl-5-oxo-N-(3-(piperidin-1-yl)propyl)thiozolo[4,5-b]pyridine-6-carboxamidepotassium salt.


14. A deuterium enriched compound of claim 1,4,5-Dihydro-7-hydroxy-4-isopropyl-5-oxo-N-(3-(piperidin-1-yl)propyl)oxazolo[4,5-b]pyridine-6-carboxamidepotassium salt.


15. A deuterium enriched compound of claim 1,4,5-Dihydro-7-hydroxy-4-isopropyl-5-oxo-N-(3-(piperidin-1-yl)propyl)oxazolo[5,4-b]pyridine-6-carboxamidepotassium salt.


16. A deuterium enriched compound of claim 1, 6,7-Dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamidepotassium salt.


17. A deuterium enriched compound of claim 1,4,5-Dihydro-7-hydroxy-4-isopropyl-5-oxo-N-(3-(piperidin-1-yl)propyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carboxamidepotassium salt.


18. A deuterium enriched compound of claim 1,1-Ethyl-1,2-dihydro-4-hydroxy-N-(3-(4-deuteromethylpiperidin-1-yl)propyl)-2-oxoquinoline-3-carboxamidepotassium salt.


19. A pharmaceutical composition comprising: a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a deuteriumenriched compound of claim 1 or a pharmaceutically acceptable salt formthereof, administered alone or in combination with donepezil ormemantine, orally, or intravenously, or via nasal inhalation.
 20. Amethod of treating Alzheimer's disease, cognitive impairment associatedwith schizophrenia, frontotemporal dementia (FTD), mild cognitionimpairment, cognitive impairment associated with age-related dementia orAlzheimer's disease, cognitive impairment associated with depression,cognitive impairment associated with post-coronary bypass surgery,attention deficit hyperactivity disorder, speech improvement in autisticchildren, sleep apnea in Alzheimer's patients, irritable bowel syndrome,gastroesophageal reflux disease, Crohn's disease, emesis, nausea,vomiting, prokinesia, non-ulcer dyspepcia, anxiety, depression, pain,migraine, urinary incontinence, arterial fibrillation, arrhythmia,ischemic stroke, gastric emptying disorders, gastritis, gastrointestinaldisorders, feeding disorders, obesity, anorexia, constipation,respiratory depression, and erectile dysfunction, comprisingadministering to humans in need of such treatment an effective amount ofa compound of formula I, or pharmaceutically acceptable salt thereof.